Method of treating addictions to opioids

ABSTRACT

A pharmaceutical composition containing isomyosmine or a pharmaceutically acceptable salt thereof is administered to an individual in need thereof for treating a substance addiction, inclusive of addiction to heroin (diacetylmorphine), cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine. The isomyosmine, along with optional additional therapeutic agent(s), may be administered in a capsule, tablet, or lozenge.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.15/670,012, filed Aug. 7, 2017, now U.S. Pat. No. 9,884,055, which is acontinuation-in-part of International Application PCT/US2016/018047,filed Feb. 16, 2016, which claims priority under 35 U.S.C. § 119(e) toU.S. Provisional Application No. 62/118,136, filed Feb. 19, 2015, thedisclosures of which are hereby incorporated by reference in theirentireties.

BACKGROUND

Monoamine oxidase (MAO) inhibitors can regulate the level of monoaminesand their neurotransmitter release in different brain regions and in thebody (including dopamine, norepinephrine, and serotonin). MAO inhibitors(MAOI) can thereby affect the modulation of neuroendocrine function,respiration, mood, motor control and function, focus and attention,concentration, memory and cognition, and the mechanisms of substanceabuse. MAOI have been demonstrated to have effects on attention,cognition, appetite, substance abuse, memory, cardiovascular function,extrapyramidal function, pain and gastrointestinal motility andfunction. The distribution of MAO in the brain is widespread andincludes the basal ganglia, cerebral cortex, limbic system, and mid andhind brain nuclei. In the peripheral tissue, the distribution includesmuscle, the gastrointestinal tract, the cardiovascular system, autonomicganglia, the liver, and the endocrinic system. Regulation of monoaminelevels in the body has been shown to be effective in numerous diseasestates including depression, anxiety, stress disorders, and withdrawalsymptoms, among others.

It has been suggested that cigarette smoke may have irreversibleinhibitory effect towards monoamine oxidase (MAO). A. A. Boulton et al.,“Biogenic Amine Adducts, Monoamine Oxidase Inhibitors, and Smoking,”Lancet, 1 (8577):114-155 (1988), reported that the MAO inhibitingproperties of cigarette smoke may help to explain the protective actionof smoking against Parkinson's disease and also observed that patientswith mental disorders who smoke heavily do not experience unusual ratesof smoking induced disorders. It was suggested that smoking, as an MAOI,may protect against dopaminergic neurotoxicity that leads to Parkinson'sdisease and that the MAO inhibiting properties of smoking may result inan anti-depressive effect in mental patients.

L. A. Carr et al., “Effects of Tobacco Smoke Constituents onMPTP-Induced Toxicity and Monoamine Oxidase Activity in the MouseBrain,” Life Sciences, 48:1173 1177 (1991), found that nicotine,4-phenylpyridine and hydrazine prevented the decrease in dopaminemetabolite levels induced by1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, but therewas no significant effect on dopamine levels. Because tobacco smokeparticulate matter caused a marked inhibition of MAO-A and MAO-Bactivity when added in vitro, it was suggested that one or moreunidentified substances in tobacco smoke are capable of inhibiting brainMAO and perhaps altering the formation of the active metabolite of MPTP.

J. S. Fowler et al., “Inhibition of Monoamine Oxidase B in the Brain ofSmokers,” Nature (Lond), 379(6567): 733 736 (1996), found that thebrains of living smokers showed a 40% decrease in the level of MAO-Brelative to nonsmokers or former smokers. MAO inhibition was alsoreported as being associated with decreased production of hydrogenperoxide.

It has also been suggested that nicotine may not be the only constituentof tobacco responsible for tobacco addiction. J. Stephenson, “CluesFound to Tobacco Addiction,” Journal of the American MedicalAssociation, 275(16): 1217 1218 (1996), discussing the work of Fowler,et al., pointed out that the brains of living smokers had less MAO-Bcompared with the brains of nonsmokers or former smokers. MAO-B is anenzyme involved in the breakdown of dopamine, which is apleasure-enhancing neurotransmitter. The results suggested that theinhibition of MAO-B in the brains of smokers may make nicotine moreaddictive by slowing down the breakdown of dopamine, thereby boostingits levels. The findings provided an explanation as to why cigarettesmokers were less susceptible to developing Parkinson's disease.Further, the findings suggested that MAOI could be used for smokingcessation. Williams et al. U.S. Pat. No. 6,350,479 reported that theminor tobacco alkaloids anabasine, anatabine, and nornicotine exhibitedMAO inhibitory effects against MAO-A and MAO-B.

There remains a need for alternative therapies for treating substanceaddictions and for assisting individuals in reducing or eliminatingcravings for nicotine or dependence on nicotine.

SUMMARY

In accordance with aspects disclosed herein, compositions containingisomyosmine or a pharmaceutically acceptable salt thereof may beadministered to an individual in need thereof for treating substanceaddiction, such as tobacco- or other substance addiction, includingsmoking addiction, smokeless tobacco addiction, and other forms ofnicotine dependence. A substance addiction may be, example, an addictionto heroin (diacetylmorphine), cocaine, opioids, methadone,d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines,or buprenorphine. In some examples, isomyosmine or a pharmaceuticallyacceptable salt thereof is administered, with or without other activeagent(s), in a capsule, tablet, or lozenge. In other examples,isomyosmine or a pharmaceutically acceptable salt thereof isadministered, with or without other active agent(s), via a chewing gum,inhalation spray, e-cigarette, or transdermal patch.

The present inventor found that isomyosmine is a potent inhibitor ofmonoamine oxidase (MAO), including both MAO-A and MAO-B. Through theseand/or other mechanisms (e.g., anti-inflammatory properties),isomyosmine may be particularly effective for treating substanceaddiction, inclusive of affecting smoking substitution and/or assistingindividuals in reducing or eliminating cravings for nicotine ordependence on nicotine.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention and certainadvantages thereof may be acquired by referring to the followingdetailed description in consideration with the accompanying drawings, inwhich:

FIG. 1 is a graph showing the ability of isomyosmine, myosmine,anatabine, anabasine, and nornicotine to inhibit the enzymatic activityof MAO-A.

FIG. 2 is a graph showing the ability of isomyosmine, myosmine,anatabine, anabasine, and nornicotine to inhibit the activity of MAO-B.

FIG. 3 is a graph showing oxygen saturation (%) in individuals beforeand one hour after oral administration of isomyosmine.

DETAILED DESCRIPTION

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutically acceptable”means any molecular entity or composition that does not produce anadverse, allergic or other untoward or unwanted reaction whenadministered to an individual. As used herein, the term“pharmaceutically acceptable composition” is synonymous with“pharmaceutical composition” and means a therapeutically effectiveconcentration of an active ingredient, such as any of the therapeuticcompounds disclosed herein. A pharmaceutical composition may beadministered to an individual alone, or in combination with othersupplementary active ingredients, agents, drugs or hormones.

A pharmaceutical composition disclosed herein may include apharmaceutically acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically acceptable compositions. As usedherein, the term “pharmacologically acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or“excipient.” Such a carrier generally is mixed with an active compoundor permitted to dilute or enclose the active compound and can be asolid, semi-solid, or liquid agent. It is understood that the activeingredients can be soluble or can be delivered as a suspension in thedesired carrier or diluent. Any of a variety of pharmaceuticallyacceptable carriers can be used including, without limitation, aqueousmedia such as, e.g., water, saline, glycine, hyaluronic acid and thelike; solid carriers such as, e.g., mannitol, lactose, starch, magnesiumstearate, sodium saccharin, talcum, cellulose, glucose, sucrose,magnesium carbonate, and the like; solvents; dispersion media; coatings;antibacterial and antifungal agents; isotonic and absorption delayingagents; or any other inactive ingredient. Selection of apharmacologically acceptable carrier can depend on the mode ofadministration. Except insofar as any pharmacologically acceptablecarrier is incompatible with the active ingredient, its use inpharmaceutically acceptable compositions is contemplated. Non-limitingexamples of specific uses of such pharmaceutical carriers can be foundin Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C.Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed.1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R.Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman &Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman etal., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook ofPharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications,4th edition 2003). These protocols are routine procedures and anymodifications are well within the scope of one skilled in the art andfrom the teaching herein.

Unless otherwise clear from context, all percentages referred to hereinare expressed as percent by weight based on the total weight of thecomposition. Percentages expressed herein as “w/v” refer to mass, ingrams, of the component per 100 ml of solvent. For example, a 1% (w/v)composition of isomyosmine contains 1 g (1000 mg) of isomyosmine per 100ml of solvent, which is equivalent to 10 mg/ml.

Isomyosmine (3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine) is a nicotinerelated alkaloid present in solanecea plants containing nicotine.

Isomyosmine may be prepared synthetically using known techniques, andalso is commercially available from several chemical suppliers.Isomyosmine has two optical isomers (+/−) owing to an asymmetric carbonatom within its pyrrole ring that joins to the pyridine ring. Unlessotherwise clear from context, the term “isomyosmine,” as used herein, isinclusive of enantiomeric mixtures (+/−) including racemic mixtures, aswell as isolated forms of one or the other enantiomer.

In some embodiments, isomyosmine may be adsorbed on a cation exchangeresin such as polymethacrilic acid (Amberlite IRP64 or PuroliteC115HMR), as described in U.S. Pat. No. 3,901,248, the disclosure ofwhich is hereby incorporated by reference in its entirety. Such cationexchange resins have been used commercially, for example, in nicotinereplacement therapy, e.g., nicotine polacrilex.

Unless otherwise clear from context, “isomyosmine” as used herein refersto both salt and non-salt forms of isomyosmine. Non-limiting examples ofpossible salts are described in P. H. Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection and Use,Weinheim/Zürich:Wiley-VCH/VHCA, 2002, including salts of1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid(DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,toluenesulfonic acid (p), and undecylenic acid.

As an alternative to synthetic preparation, isomyosmine may be obtainedby extraction from tobacco or other materials in which it occursnaturally. For example, tobacco material may extracted with a solvent,such as water, ethanol, steam, and/or carbon dioxide. The resultingsolution contains the soluble components of the tobacco, includingalkaloids such as nicotine, isomyosmine, and myosmine. Isomyosmine (aswell as other extracted components, such as nicotine, if desired) may bepurified using known techniques such as liquid chromatography. Nicotineand/or other alkaloid components, when used, likewise may be preparedsynthetically or extracted from appropriate natural materials.

In pharmaceutical applications, an isolated form of isomyosminegenerally is used. An “isolated form of isomyosmine,” as used herein,refers to isomyosmine that either has been prepared synthetically or hasbeen substantially separated from natural materials in which it occurs.The isolated form of isomyosmine should have a very high purity(including enantiomeric purity in the case where an enantiomer is used).In the case of synthetic isomyosmine, for example, purity refers to theratio of the weight of isomyosmine to the weight of the end reactionproduct. In the case of isolating isomyosmine from native material, forexample, purity refers to the ratio of the weight of isomyosmine to thetotal weight of the isomyosmine-containing extract. Usually, the levelof purity is at least about 95%, more usually at least about 96%, about97%, about 98%, or higher. For example, the level of purity may be about98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%,99.9%, or higher.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

Compositions may contain isomyosmine, alone or with other therapeuticcompound(s). A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. A therapeuticcompound disclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g., a hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Insome aspects, the therapeutic compound may have anti-inflammatoryactivity, such as a non-steroidal anti-inflammatory drug (NSAID). NSAIDsare a large group of therapeutic compounds with analgesic,anti-inflammatory, and anti-pyretic properties. NSAIDs reduceinflammation by blocking cyclooxygenase. NSAIDs include, withoutlimitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen,amfenac, aloxipirin, aminophenazone, antraphenine, aspirin,azapropazone, benorilate, benoxaprofen, benzydamine, butibufen,celecoxib, chlorthenoxacin, choline salicylate, clometacin,dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac,etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen,glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen,ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib,mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone,mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin,phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone,protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen,tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

NSAIDs may be classified based on their chemical structure or mechanismof action. Non-limiting examples of NSAIDs include a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclooxygenase (COX) inhibitor, a selective cyclooxygenase-1 (COX-1)inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor. An NSAIDmay be a profen. Examples of a suitable salicylate derivative NSAIDinclude, without limitation, acetylsalicylic acid (aspirin), diflunisal,and salsalate. Examples of a suitable p-amino phenol derivative NSAIDinclude, without limitation, paracetamol and phenacetin. Examples of asuitable propionic acid derivative NSAID include, without limitation,alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin,pranoprofen, and suprofen. Examples of a suitable acetic acid derivativeNSAID include, without limitation, aceclofenac, acemetacin, actarit,alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac,fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac,nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of asuitable enolic acid (oxicam) derivative NSAID include, withoutlimitation, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, andtenoxicam. Examples of a suitable fenamic acid derivative NSAID include,without limitation, flufenamic acid, mefenamic acid, meclofenamic acid,and tolfenamic acid. Examples of a suitable selective COX-2 inhibitorsinclude, without limitation, celecoxib, etoricoxib, firocoxib,lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

Isomyosmine may be administered for treating tobacco or other substanceaddiction, including promoting smoking cessation or otherwise assistingindividuals in reducing or eliminating cravings for nicotine ordependence on nicotine. Isomyosmine was found to be a potent inhibitorof monoamine oxidase (MAO), including both MAO-A and MAO-B. Throughthese and/or other mechanisms, pharmaceutical compositions containingisomyosmine may be particularly effective for treating tobacco addictionand/or for assisting individuals in reducing or eliminating cravings fornicotine or dependence on nicotine.

A therapeutic compound disclosed herein may be an ester of a therapeuticcompound. In general, an ester of a therapeutic compound increases thelog P value relative to the same therapeutic compound without the estermodification. An ester group may be attached to a therapeutic compoundby, e.g., a carboxylic acid or hydroxyl functional group present of thetherapeutic compound. An ester of a therapeutic compound may have anincreased hydrophobicity, and as such, may be dissolved in a reducedvolume of solvent disclosed herein. In some instances, an ester of atherapeutic compound may be combined directly with an adjuvant disclosedherein, thereby eliminating the need of a solvent. An ester of atherapeutic compound may enable the making of a pharmaceuticalcomposition disclosed herein, in situations where a non-esterified formof the same therapeutic compound is otherwise immiscible in a solventdisclosed herein. An ester of a therapeutic compound may still bedelivered in a manner that more effectively inhibits a pro-inflammatoryresponse as long as the compound is combined with an adjuvant disclosedherein. In one embodiment, a therapeutic compound may be reacted withethyl ester in order to form an ethyl ester of the therapeutic compound.

A pharmaceutical composition may comprise a therapeutic compound in anamount sufficient to allow customary administration to an individual. Inaspects of this embodiment, a pharmaceutical composition disclosedherein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, atleast 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, atleast 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeuticcompound. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may be, e.g., at least 5 mg, at least 10mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, atleast 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, atleast 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, atleast 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg,at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of atherapeutic compound. In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg,about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mgto about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg toabout 1,500 mg. In still other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg,about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mgto about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg,about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg toabout 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000mg, or about 5 mg to about 250 mg.

Pharmaceutical compositions as described herein may include apharmaceutically acceptable solvent. A solvent is a liquid, solid, orgas that dissolves another solid, liquid, or gaseous (the solute),resulting in a solution. Solvents useful in the pharmaceuticalcompositions include, without limitation, a pharmaceutically acceptablepolar aprotic solvent, a pharmaceutically acceptable polar proticsolvent and a pharmaceutically acceptable non-polar solvent. Apharmaceutically acceptable polar aprotic solvent includes, withoutlimitation, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate,acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO). A pharmaceutically acceptable polar protic solventincludes, without limitation, acetic acid, formic acid, ethanol,n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol,n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.A pharmaceutically acceptable non-polar solvent includes, withoutlimitation, pentane, cyclopentane, hexane, cyclohexane, benzene,toluene, 1,4-dioxane, chloroform, n-methyl-pyrrilidone (NMP), anddiethyl ether.

A pharmaceutical composition disclosed herein may comprise a solvent inan amount sufficient to dissolve a therapeutic compound disclosedherein. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may comprise a solvent in an amount of,e.g., less than about 90% (v/v), less than about 80% (v/v), less thanabout 70% (v/v), less than about 65% (v/v), less than about 60% (v/v),less than about 55% (v/v), less than about 50% (v/v), less than about45% (v/v), less than about 40% (v/v), less than about 35% (v/v), lessthan about 30% (v/v), less than about 25% (v/v), less than about 20%(v/v), less than about 15% (v/v), less than about 10% (v/v), less thanabout 5% (v/v), or less than about 1% (v/v). In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise asolvent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v),about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v)to 50% (v/v), about 1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v),about 1% (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v)to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v),about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v)to 50% (v/v), about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v),about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v)to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v),about 6% (v/v) to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v)to 50% (v/v), about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v),about 8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8%(v/v) to 12% (v/v).

In one embodiment, a solvent may comprise a pharmaceutically acceptablealcohol. As used herein, the term “alcohol” refers to an organicmolecule comprising a hydroxyl functional group (—OH) bonded to a carbonatom, where the carbon atom is saturated. In aspects of this embodiment,the alcohol may be, e.g., a C1-4 alcohol, a C2-4 alcohol, a C1-5alcohol, a C1-7 alcohol, a C1-10 alcohol, a C1-15 alcohol, or a C1-20alcohol. In other aspects of this embodiment, an alcohol may be, e.g., aprimary alcohol, a secondary alcohol, or a tertiary alcohol. In otheraspects of this embodiment, an alcohol may be, e.g., an acyclic alcohol,a monohydric alcohol, a polyhydric alcohol (also known as a polyol orsugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol,or a combination thereof. Examples of a monohydric alcohol include,without limitation, methanol, ethanol, propanol, butanol, pentanol, and1-hexadecanol. Examples of a polyhydric alcohol include, withoutlimitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol,sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol),and isomalt. Examples of an unsaturated aliphatic alcohol include,without limitation, prop-2-ene-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, andprop-2-in-1-ol. Examples of an alicyclic alcohol include, withoutlimitation, cyclohexane-1,2,3,4,5,6-hexyl and2-(2-propyl)-5-methyl-cyclohexane-1-ol.

In another embodiment, a solvent may comprise an ester ofpharmaceutically acceptable alcohol and an acid. Suitablepharmaceutically acceptable alcohols include the ones disclosed herein.Suitable acids include, without limitation, acetic acid, butaric acid,and formic acid. An ester of an alcohol and an acid include, withoutlimitation, methyl acetate, methyl buterate, methyl formate, ethylacetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate,propyl formate, butyl acetate, butyl buterate, butyl formate, isobutylacetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentylbuterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate,and 1-hexadecyl formate.

In another embodiment, a solvent may comprise a pharmaceuticallyacceptable polyethylene glycol (PEG) polymer. PEG polymers, also knownas polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers,are prepared by polymerization of ethylene oxide and are commerciallyavailable over a wide range of molecular weights from 100 g/mol to10,000,000 g/mol. PEG polymers with a low molecular mass are liquids orlow-melting solids, whereas PEG polymers of a higher molecular mass aresolids. A PEG polymer include, without limitation, PEG 100, PEG 200, PEG300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG19,000, or PEG 20,000.

In another embodiment, a solvent may comprise a pharmaceuticallyacceptable glyceride. Glycerides comprise a substituted glycerol, whereone, two, or all three hydroxyl groups of the glycerol are eachesterified using a fatty acid to produce monoglycerides, diglycerides,and triglycerides, respectively. In these compounds, each hydroxylgroups of glycerol may be esterified by different fatty acids.Additionally, glycerides may be acetylated to produce acetylatedmonoglycerides, acetylated diglycerides, and acetylated triglycerides.

In one embodiment, a solvent may comprise a pharmaceutically acceptablesolid solvent. Solid solvents may be useful in the manufacture of asolid dose formulation of a pharmaceutical composition disclosed herein.Typically, a solid solvent is melted in order to dissolve a therapeuticcompound. A pharmaceutically acceptable solid solvent includes, withoutlimitation, menthol and PEG polymers described above.

Aspects of the present specification disclose, in part, apharmaceutically acceptable adjuvant. An adjuvant is a pharmacologicalagent that modifies the effect of other agents, such as one or moretherapeutic compounds disclosed herein. In addition, an adjuvantdisclosed herein may be used as a solvent that dissolves a therapeuticcompound disclosed herein, forming an adjuvant solution. An adjuvant mayfacilitate delivery of a therapeutic compound in a manner that moreeffectively inhibits a pro-inflammatory response. In one embodiment, anadjuvant facilitates the delivery of a therapeutic compound intomacrophages.

A pharmaceutical composition may comprise a pharmaceutically acceptableadjuvant in an amount sufficient to mix with a solution or an emulsion.In other aspects of this embodiment, a pharmaceutical composition maycomprise an adjuvant in an amount of, e.g., at least 10% (v/v), at least20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% (v/v),at least 45% (v/v), at least 50% (v/v), at least 55% (v/v), at least 60%(v/v), at least 65% (v/v), at least 70% (v/v), at least 75% (v/v), atleast 80% (v/v), at least 85% (v/v), at least 90% (v/v), at least 95%(v/v), or at least 99% (v/v). In other aspects of this embodiment, apharmaceutical composition may comprise an adjuvant in an amount in arange of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (v/v) toabout 99% (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) toabout 99% (v/v), about 50% (v/v) to about 99% (v/v), about 30% (v/v) toabout 98% (v/v), about 35% (v/v) to about 98% (v/v), about 40% (v/v) toabout 98% (v/v), about 45% (v/v) to about 98% (v/v), about 50% (v/v) toabout 98% (v/v), about 30% (v/v) to about 95% (v/v), about 35% (v/v) toabout 95% (v/v), about 40% (v/v) to about 95% (v/v), about 45% (v/v) toabout 95% (v/v), or about 50% (v/v) to about 95% (v/v). In yet otheraspects of this embodiment, a pharmaceutical composition may comprise anadjuvant in an amount in a range of, e.g., about 70% (v/v) to about 97%(v/v), about 75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97%(v/v), about 85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97%(v/v), about 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97%(v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96%(v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96%(v/v), about 89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96%(v/v), about 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93%(v/v), about 85% (v/v) to about 93% (v/v), about 88% (v/v) to about 93%(v/v), about 89% (v/v) to about 93% (v/v), or about 90% (v/v) to about93% (v/v).

In one embodiment, an adjuvant may be a pharmaceutically acceptablelipid. A lipid may be broadly defined as a hydrophobic or amphiphilicsmall molecule. The amphiphilic nature of some lipids allows them toform structures such as vesicles, liposomes, or membranes in an aqueousenvironment. Non-limiting examples, of lipids include fatty acids,glycerolipids (like monoglycerides, diglycerides, and triglycerides),phospholipids, sphingolipids, sterol lipids, prenol lipids,saccharolipids, and polyketides. A pharmaceutical composition disclosedherein may comprise a lipid such as, e.g. an oil, an oil-based liquid, afat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fattyalcohol, a glyceride (mono-, di- or tri-glyceride), a phospholipids, aglycol ester, a sucrose ester, a glycerol oleate derivative, a mediumchain triglyceride, or a mixture thereof.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable fatty acid. A fatty acid comprises acarboxylic acid with a long unbranched hydrocarbon chain which may beeither saturated or unsaturated. Thus arrangement confers a fatty acidwith a polar, hydrophilic end, and a nonpolar, hydrophobic end that isinsoluble in water. Most naturally occurring fatty acids have ahydrocarbon chain of an even number of carbon atoms, typically between 4and 24 carbons, and may be attached to functional groups containingoxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fattyacids may have a hydrocarbon chain of any number of carbon atoms frombetween 3 and 40 carbons. Where a double bond exists, there is thepossibility of either a cis or a trans geometric isomerism, whichsignificantly affects the molecule's molecular configuration. Cis-doublebonds cause the fatty acid chain to bend, an effect that is morepronounced the more double bonds there are in a chain. Most naturallyoccurring fatty acids are of the cis configuration, although the transform does exist in some natural and partially hydrogenated fats andoils. Examples of fatty acids include, without limitation, capryllicacid (8:0), pelargonic acid (9:0), capric acid (10:0), undecylic acid(11:0), lauric acid (12:0), tridecylic acid (13:0), myristic acid(14:0), myristoleic acid (14:1), pentadecyclic acid (15:0), palmiticacid (16:0), palmitoleic acid (16:1), sapienic acid (16:1), margaricacid (17:0), stearic acid (18:0), oleic acid (18:1), elaidic acid(18:1), vaccenic acid (18:1), linoleic acid (18:2), linoelaidic acid(18:2), α-linolenic acid (18:3), γ-linolenic acid (18:3), stearidonicacid (18:4), nonadecylic acid (19:0), arachidic acid (20:0), eicosenoicacid (20:1), dihomo-γ-linolenic acid (20:3), mead acid (20:3),arachidonic acid (20:4), eicosapentaenoic acid (20:5), heneicosylic acid(21:0), behenic acid (22:0), erucic acid (22:1), docosahexaenoic acid(22:6), tricosylic acid (23:0), lignoceric acid (24:0), nervonic acid(24:1), pentacosylic acid (25:0), cerotic acid (26:0), heptacosylic acid(27:0), montanic acid (28:0), nonacosylic acid (29:0), melissic acid(30:0), henatriacontylic acid (31:0), lacceroic acid (32:0), psyllicacid (33:0), geddic acid (34:0), ceroplastic acid (35:0), andhexatriacontylic acid (36:0).

An adjuvant may be a pharmaceutically acceptable saturated orunsaturated fatty acid. A saturated or unsaturated fatty acid maycomprise, e.g., at least 8, at least 10, at least 12, at least 14, atleast 16, at least 18, at least 20, at least 22, at least 24, at least26, at least 28, or at least 30 carbon atoms. In some instances, asaturated or unsaturated fatty acid comprises, e.g., between 4 and 24carbon atoms, between 6 and 24 carbon atoms, between 8 and 24 carbonatoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms,between 14 and 24 carbon atoms, or between 16 and 24 carbon atoms,between 4 and 22 carbon atoms, between 6 and 22 carbon atoms, between 8and 22 carbon atoms, between 10 and 22 carbon atoms, between 12 and 22carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22carbon atoms, between 4 and 20 carbon atoms, between 6 and 20 carbonatoms, between 8 and 20 carbon atoms, between 10 and 20 carbon atoms,between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, orbetween 16 and 20 carbon atoms. If unsaturated, the fatty acid may have,e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 ormore double bonds.

A pharmaceutically acceptable saturated or unsaturated fatty acid may beliquid at room temperature. The melting point of a fatty acid is largelydetermined by the degree of saturation/unsaturation of the hydrocarbonchain. In aspects of this embodiment, a saturated or unsaturated fattyacid has a melting point temperature of, e.g., 20° C. or below, 15° C.or below, 10° C. or below, 5° C. or below, 0° C. or below, −5° C. orbelow, −10° C. or below, −15° C. or below, or −20° C. or below. In otheraspects of this embodiment, a saturated or unsaturated fatty acid has amelting point temperature in the range of, e.g., about −20° C. to about20° C., about −20° C. to about 18° C., about −20° C. to about 16° C.,about −20° C. to about 12° C., about −20° C. to about 8° C., about −20°C. to about 4° C., about −20° C. to about 0° C., about −15° C. to about20° C., about −15° C. to about 18° C., about −15° C. to about 16° C.,about −15° C. to about 12° C., about −15° C. to about 8° C., about −15°C. to about 4° C., or about −15° C. to about 0° C.

An adjuvant may comprise one kind of pharmaceutically acceptable fattyacid. An adjuvant may comprise, for example, only palmitic acid, onlystearic acid, only oleic acid, only linoleic acid, or only linolenicacid. Alternatively, an adjuvant may comprise a plurality of differentpharmaceutically acceptable fatty acids. An adjuvant may comprise, e.g.,two or more different fatty acids, three or more different fatty acids,four or more different fatty acids, five or more different fatty acids,or six or more different fatty acids.

An adjuvant may comprise two or more different pharmaceuticallyacceptable fatty acids including at least palmitic acid, stearic acid,oleic acid, linoleic acid and/or linolenic acid, and any combinationthereof. An adjuvant may comprise a ratio of palmitic acid and/orstearic acid and/or oleic acid:linolenic acid and/or linoleic acid of,e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least15:1, or at least 20:1. In some examples, an adjuvant may comprise aratio of palmitic acid and/or stearic acid and/or oleic acid:linolenicacid and/or linoleic acid in a range of, e.g., about 1:1 to about 20:1,about 2:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 to about10:1.

An adjuvant may comprise four or more different pharmaceuticallyacceptable fatty acids including at least palmitic acid, stearic acid,oleic acid, linoleic acid and/or linolenic acid, and any combinationthereof. In other aspects of this embodiment, an adjuvant may comprise aratio of palmitic acid:stearic acid:linolenic acid:linoleic acid of,e.g., 10:10:1:1, 9:9:1:1, 8:8:1:1, 7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1,3:3:1:1, 2:2:1:1, or 1:1:1:1. In other aspects of this embodiment, anadjuvant may comprise a ratio of palmitic acid:stearic acid:linolenicacid:linoleic acid in a range of, e.g., about 10:10:1:1 to about6:6:1:1, about 8:8:1:1 to about 4:4:1:1, or about 5:5:1:1 to about1:1:1:1.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable omega fatty acid. Non-limiting examples ofan omega fatty acid include omega-3, omega-6, and omega-9. Omega-3 fattyacids (also known as n-3 fatty acids or ω-3 fatty acids) are a family ofessential unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-3 position, that is, the third bond,counting from the methyl end of the fatty acid. The omega-3 fatty acidsare “essential” fatty acids because they are vital for normal metabolismand cannot be synthesized by the human body. An omega-3 fatty acidincludes, without limitation, hexadecatrienoic acid (16:3), α-linolenicacid (18:3), stearidonic acid (18:4), eicosatrienoic acid (20:3),eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5),heneicosapentaenoic acid (21:5), docosapentaenoic acid (22:5),clupanodonic acid (22:5), docosahexaenoic acid (22:6),tetracosapentaenoic acid (24:5), and tetracosahexaenoic acid (nisinicacid) (24:6).

Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-6 position, that is, the sixth bond,counting from the methyl end of the fatty acid. An omega-6 fatty acidincludes, without limitation, linoleic acid (18:2), gamma-linolenic acid(18:3), calendic acid (18:3), eicosadienoic acid (20:2),dihomo-gamma-linolenic acid (20:3), arachidonic acid (20:4),docosadienoic acid (22:2), adrenic acid (22:4), docosapentaenoic acid(22:5), tetracosatetraenoic acid (24:4), and tetracosapentaenoic acid(24:5). Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fattyacids) are a family of unsaturated fatty acids that have in common afinal carbon-carbon double bond in the n-9 position, that is, the ninthbond, counting from the methyl end of the fatty acid. An omega-9 fattyacid includes, without limitation, oleic acid (18:1), elaidic acid(18:1), eicosenoic acid (20:1), mead acid (20:3), erucic acid (22:1),and nervonic acid (24:1).

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically acceptable oil. An oil includes any fatty acidthat is liquid at normal room temperature, such as, e.g. about 20° C. Incontrast, a fat includes any fatty acid that is solid at normal roomtemperature, such as, e.g. about 20° C. An oil suitable as a lipiduseful in the pharmaceutical compositions disclosed herein, may be anatural oil or a vegetable oil. Examples of suitable natural oilsinclude, without limitation, mineral oil, triacetin, ethyl oleate, ahydrogenated natural oil, or a mixture thereof. Examples of suitablevegetable oils include, without limitation, almond oil, arachis oil,avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseedoil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seedoil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil,safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnutoil, wheat germ oil, or a mixture thereof. Each of these oils iscommercially available from a number of sources well recognized by thoseskilled in the art.

An oil is typically a mixture of various fatty acids. For example,rapeseed oil, obtained from the seeds of brassica napus, includes bothomega-6 and omega-3 fatty acids in a ratio of about 2:1. As anotherexample, linseed oil, obtained from the seeds of linum usitatissimum,includes about 7% palmitic acid, about 3.4-4.6% stearic acid, about18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about51.9-55.2% α-linolenic acid. In some instances, a pharmaceuticalcomposition comprises an oil including at least two different fattyacids, at least three different fatty acids, at least four differentfatty acids, at least five different fatty acids, or at least sixdifferent fatty acids.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable glycerolipid. Glycerolipids are composedmainly of mono-, di-, and tri-substituted glycerols. One group ofglycerolipids is the glycerides, where one, two, or all three hydroxylgroups of glycerol are each esterified using a fatty acid to producemonoglycerides, diglycerides, and triglycerides, respectively. In thesecompounds, each hydroxyl groups of glycerol may be esterified bydifferent fatty acids. Additionally, glycerides may be acetylated toproduce acetylated monoglycerides, acetylated diglycerides, andacetylated triglycerides. One group of glycerolipids is the glycerides,where one, two, or all three hydroxyl groups of glycerol have sugarresidues attached via a glycosidic linkage.

In some instances, compositions may include one or more pharmaceuticallyacceptable stabilizing agents. A stabilizing agent reduces or eliminatesformation of esters of a therapeutic compound that may result as aunwanted reaction with the particular solvent used. A stabilizing agentinclude, without limitation, water, a sacrificial acid comprising afatty acid component and acetic acid, ethyl acetate, a sodiumacetate/acetic acid (E262), a monoglyceride, an acetylatedmonoglyceride, a diglyceride, an acetylated monoglyceride, an acetylateddiglyceride, a fatty acid, and a fatty acid salt.

In one embodiment, a pharmaceutically acceptable stabilizing agent maycomprise a pharmaceutically acceptable emulsifying agent. An emulsifyingagent (also known as an emulgent) is a substance that stabilizes anemulsion comprising a liquid dispersed phase and a liquid continuousphase by increasing its kinetic stability. Thus, in situations where thesolvent and adjuvant used to make a pharmaceutical composition disclosedherein are normally immiscible, an emulsifying agent disclosed herein isused to create a homogenous and stable emulsion. An emulsifying agentincludes, without limitation, a surfactant, a polysaccharide, a lectin,and a phospholipid.

An emulsifying agent may comprise a surfactant. As used hereon, the term“surfactant” refers to a natural or synthetic amphiphilic compound. Asurfactant can be non-ionic, zwitterionic, or ionic. Non-limitingexamples of surfactants include polysorbates like polysorbate 20 (TWEEN®20), polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate61 (TWEEN® 61), polysorbate 65 (TWEEN® 65), polysorbate 80 (TWEEN® 80),and polysorbate 81 (TWEEN® 81); poloxamers (polyethylene-polypropylenecopolymers), such as Poloxamer 124 (PLURONIC® L44), Poloxamer 181(PLURONIC® L61), Poloxamer 182 (PLURONIC® L62), Poloxamer 184 (PLURONIC®L64), Poloxamer 188 (PLURONIC® F68), Poloxamer 237 (PLURONIC® F87),Poloxamer 338 (PLURONIC® L108), Poloxamer 407 (PLURONIC® F127),polyoxyethyleneglycol dodecyl ethers, such as BRIJ® 30, and BRIJ® 35;2-dodecoxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether(TRITON® X-100); sodium dodecyl sulfate (SDS);3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS);3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate(CHAPSO); sucrose monolaurate; and sodium cholate. Other non-limitingexamples of surfactant excipients can be found in, e.g., Ansel, supra,(1999); Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, supra,(2003), each of which is hereby incorporated by reference in itsentirety.

An emulsifying agent may comprise a polysaccharide. Non-limitingexamples of polysaccharides include guar gum, agar, alginate, calgene, adextran (like dextran 1K, dextran 4K, dextran 40K, dextran 60K, anddextran 70K), dextrin, glycogen, inulin, starch, a starch derivative(like hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch,hydroxybutyl starch, and hydroxypentyl starch), hetastarch, cellulose,FICOLL, methyl cellulose (MC), carboxymethyl cellulose (CMC),hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxyethyl methyl cellulose (NEMC), hydroxypropyl methyl cellulose(HPMC); polyvinyl acetates (PVA); polyvinyl pyrrolidones (PVP), alsoknown as povidones, having a K-value of less than or equal to 18, aK-value greater than 18 or less than or equal to 95, or a K-valuegreater than 95, like PVP 12 (KOLLIDON® 12), PVP 17 (KOLLIDON® 17), PVP25 (KOLLIDON® 25), PVP 30 (KOLLIDON® 30), PVP 90 (KOLLIDON® 90); andpolyethylene imines (PEI).

An emulsifying agent may comprise a lectin. Lectins are sugar-bindingproteins that are highly specific for their sugar moieties. Lectins maybe classified according to the sugar moiety that they bind to, andinclude, without limitation, mannose-binding lectins,galactose/N-acetylgalactosamine-binding lectins,N-acetylgluxosamine-binding lectins, N-acetylneuramine-binding lectins,N-acetylneuraminic acid-binding lectins, and fucose-binding lectins.Non-limiting examples of surfactants include concanavain A, lentillectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairy vetchlectin, wheat germ agglutinin, elderberry lectin, Maackia anurensisleukoagglutinin, Maackia anurensis hemoagglutinin, Ulex europaeusagglutinin, and Aleuria aurantia lectin.

An emulsifying agent may comprise a phospholipid. The structure of thephospholipid generally comprises a hydrophobic tail and a hydrophilichead and is amphipathic in nature. Most phospholipids contain adiglyceride, a phosphate group, and a simple organic molecule such ascholine; one exception to this rule is sphingomyelin, which is derivedfrom sphingosine instead of glycerol. Phospholipids include, withoutlimitation, diacylglycerides and phosphosphingolipids. Non-limitingexamples of diacylglycerides include a phosphatidic acid (phosphatidate)(PA), a phosphatidylethanolamine (cephalin) (PE), a phosphatidylcholine(lecithin) (PC), a phosphatidylserine (PS), and a phosphoinositideincluding phosphatidylinositol (PI), phosphatidylinositol phosphate(PIP), phosphatidylinositol bisphosphate (PIP2), andphosphatidylinositol triphosphate (PIP3). Non-limiting examples ofphosphosphingolipids include a ceramide phosphorylcholine(sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin)(Cer-PE), and ceramide phosphorylglycerol.

The final concentration of a therapeutic compound in a pharmaceuticalcomposition disclosed herein may vary over a wide range and generallymay be characterized as a therapeutically effective amount. In someaspects, the final concentration of a therapeutic compound in apharmaceutical composition may be, e.g., at least 0.00001 mg/mL, atleast 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, atleast 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200mg/mL. In other aspects of this embodiment, the concentration of atherapeutic compound disclosed herein in the solution may be, e.g., atmost 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects ofthis embodiment, the final concentration of a therapeutic compound in apharmaceutical composition may be in a range of, e.g., about 0.00001mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL,about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL toabout 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL,about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL toabout 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mLto about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL,about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL toabout 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL toabout 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mLto about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL toabout 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mLto about 100 mg/mL.

A pharmaceutical composition produced using the methods disclosed hereinmay be a liquid formulation or a solid or semi-solid formulation. Aliquid formulation can be formed by using various lipids like oils ofother fatty acids that remain as liquids in the temperature rangedesired. In an embodiment, a pharmaceutical composition disclosed hereinis liquid at room temperature. In aspects of this embodiment, apharmaceutical composition disclosed herein may be formulated to be aliquid at a temperature of, e.g., about 25° C. or higher, about 23° C.or higher, about 21° C. or higher, about 19° C. or higher, about 17° C.or higher, about 15° C. or higher, about 12° C. or higher, about 10° C.or higher, about 8° C. or higher, about 6° C. or higher, about 4° C. orhigher, or about 0° C. or higher.

A solid or semi-solid formulation may take advantage of the differentmelting point temperatures of the various adjuvants like fatty acids.Formation of a solid or semi-solid dosage form can be by modifying therespective concentrations of the fatty acids comprising a pharmaceuticalcomposition disclosed herein. For example, linolenic acid has a meltingpoint temperature (Tm) of about −11° C., linoleic acid has a Tm of about−5° C., oleic acid has a Tm of about 16° C., palmitic acid has a Tm ofabout 61-62° C., and Stearic acid has a Tm of about 67-72° C. Increasingthe proportion(s) of palmitic, stearic or oleic acid would increase theoverall melting temperature of a composition, while, conversely,increasing the proportion(s) of linoleic and linolenic acid woulddecrease the melting temperature of a composition. Thus, by controllingthe types and amounts of the adjuvant components added, a pharmaceuticalcomposition disclosed herein can be made that is substantially solid orsemi-solid at room temperature, but melts when it is ingested, andreaches body temperature. The resulting melted composition readily formsmicelles which are absorbed by the intestine, assembled intochylomicrons, and ultimately absorbed by macrophages. The solid dosageform may be a powder, granule, tablet, capsule or suppository.

In some aspects, a pharmaceutical composition may be formulated as achewing gum. The formulation of gum bases can vary substantiallydepending on the particular product to be prepared and on the desiredmasticatory and other sensory characteristics of the final product. Byway of example, typical ranges of the gum base components include 5-80wt. % elastomeric compounds, 5-80 wt. % natural and/or synthetic resins(elastomer plasticizers), 0-40 wt. % waxes, 5-35 wt. % softener otherthan waxes, 0-50 wt. % filler, and 0-5 wt. % of other ingredients suchas antioxidants, colorants, and the like. The gum base may compriseabout 5-95 wt. % of the total weight of the chewing gum, often fromabout 10-60 wt. % or from about 40-50 wt. %.

Often a buffer is used. Examples of buffers that may be used includetris buffers, amino acid buffers, carbonate, including monocarbonate,bicarbonate or sesquicarbonate, glycerinate, phosphate,glycerophosphate, acetate, glyconate or citrate of an alkali metal, suchas potassium and sodium, e.g. trisodium and tripotassium citrate, orammonium, and mixtures thereof. Other examples of buffers include aceticacid, adipic acid, citric acid, fumaric acid, glucono-δ-lactone,gluconic acid, lactic acid, malic acid, maleic acid, tartaric acid,succinic acid, propionic acid, ascorbic acid, phosphoric acid, sodiumorthophosphate, potassium orthophosphate, calcium orthophosphate, sodiumdiphosphate, potassium diphosphate, calcium diphosphate, pentasodiumtriphosphate, pentapotassium triphosphate, sodium polyphosphate,potassium polyphosphate, carbonic acid, sodium carbonate, sodiumbicarbonate, potassium carbonate, calcium carbonate, magnesiumcarbonate, magnesium oxide, or any combination thereof.

The buffer may to some extent be microencapsulated or otherwise coatedas granules with polymers and/or lipids being less soluble in salivathan is the one or more buffering agents. Such microencapsulationcontrols the dissolution rate whereby is extended the time frame of thebuffering effect. The amount of buffer may range from 0 to about 15% andoften ranges from about 0.5 to about 10% based on the total weight ofthe chewing gum.

Elastomers may be used to provide a rubbery, cohesive nature to the gum.Elastomers suitable for use in the gum base and gum may include naturalor synthetic types. Elastomer plasticizers may be used to vary thefirmness of the gum base. Their specificity on elastomer inter-molecularchain interaction (plasticizing) along with their varying softeningpoints cause varying degrees of finished gum firmness and compatibilitywhen used in base. This may provide more elastomeric chain exposure tothe alkane chains of the waxes.

The elastomers employed in the gum base may vary depending upon variousfactors such as the type of gum base desired, the texture of gumformulation desired and the other components used in the formulation tomake the final chewing gum product. The elastomer may be anywater-insoluble polymer known in the art, and includes those gumpolymers utilized for chewing gums and bubble gums. For example,polymers suitable for use in gum bases include, without limitation,natural substances (of vegetable origin) such as chicle gum, naturalrubber, crown gum, nispero, rosidinha, jelutong, perillo, niger gutta,tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and the like,and mixtures thereof. Examples of synthetic elastomers include, withoutlimitation, styrene-butadiene copolymers (SBR), polyisobutylene,isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate and thelike, and mixtures thereof.

Natural resins may be used according to the invention and may be naturalrosin esters, often referred to as ester gums including as examplesglycerol esters of partially hydrogenated rosins, glycerol esters ofpolymerized rosins, glycerol esters of partially dimerized rosins,glycerol esters of tally oil rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins, pentaerythritol esters of rosins, syntheticresins such as terpene resins derived from alpha-pinene, beta-pinene,and/or d-limonene, and natural terpene resins.

Resins may be selected from terpene resins, such as those derived fromalpha-pinene, beta-pinene, and/or d-limonene, natural terpene resins,glycerol esters of gum rosins, tall oil rosins, wood rosins or otherderivatives thereof such as glycerol esters of partially hydrogenatedrosins, glycerol esters of polymerized rosins, glycerol esters ofpartially dimerized rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins or pentaerythritol esters of rosins andcombinations thereof.

Other chewing gum ingredients may be selected from bulk sweeteners,flavors, dry-binders, tableting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, buffers, high intensitysweeteners, softeners, colors, and combinations thereof. Non-limitingexamples of emulsifiers include cyclodextrins, polyoxyethylene castoroil derivatives, polyoxyethylene alkyl ethers, macrogol alkyl ethers,block copolymers of ethylene and propylene oxides, polyoxyethylene alkylethers, polyoxyethylene glycols, polyoxyethylene sorbitan fatty acidesters, polyoxyethylene (20) sorbitan monostearates, polyoxyethylene(20) sorbitan monooleates, polyoxyethylene stearates, sobitan esters,diacetyl tartaric ester of monoglycerides, lactylated monoglycerides,and combinations thereof. The amount of emulsifiers often ranges fromabout 0.1% to about 25 wt. % based on the total weight of the chewinggum.

Petroleum waxes aid in the curing of the finished gum made from the gumbase as well as improve shelf life and texture. Wax crystal sizeinfluences the release of flavor. Those waxes high in iso-alkanes have asmaller crystal size than those waxes high in normal-alkanes, especiallythose with normal-alkanes of carbon numbers less than 30. The smallercrystal size allows slower release of flavor since there is morehindrance of the flavor's escape from this wax versus a wax havinglarger crystal sizes. The compatibility of gum bases made usingnormal-alkanic waxes is less when compared to gum bases made withiso-alkanic waxes.

Petroleum wax (refined paraffin and microcrystalline wax) and paraffinwax are composed of mainly straight-chained normal-alkanes and branchediso-alkanes. The ratio of normal-alkanes to iso-alkanes varies.

The normal-alkanic waxes typically have carbon chain lengths >C-18 butthe lengths are not predominantly longer than C-30. The branched andring structures are located near the end of the chain for those waxesthat are predominantly normal-alkanic. The viscosity of normal-alkanicwaxes is <10 mm²/s (at 100° C.) and the combined number averagemolecular weight is <600 g/mole.

The iso-alkanic waxes typically have carbon lengths that arepredominantly greater than C-30. The branched chains and ring structuresare located randomly along the carbon chain in those waxes that arepredominantly iso-alkanic. The viscosity of iso-alkanic waxes is greaterthan 10 mm²/s (at 100° C.) and the combined number average molecularweight is >600 g/mole. Synthetic waxes are produced by means that areatypical for petroleum wax production and are thus not consideredpetroleum wax. The synthetic waxes may include waxes containing branchedalkanes and copolymerized with monomers such as, but not limited topropylene, polyethylene, and Fischer Tropsch type waxes. Polyethylenewax is a synthetic wax containing alkane units of varying lengths havingattached thereto ethylene monomers.

Waxes and fats are conventionally used for the adjustment of the textureand for softening of the chewing gum base when preparing chewing gumbases. Any conventionally used and suitable type of natural andsynthetic wax and fat may be used, such as for instance rice bran wax,polyethylene wax, petroleum wax (refined paraffin and microcrystallinewax), sorbitan monostearate, tallow, propylene glycol, paraffin,beeswax, carnauba wax, candelilla wax, cocoa butter, degreased cocoapowder and any suitable oil or fat, such as completely or partiallyhydrogenated vegetable oils or completely or partially hydrogenatedanimal fats.

Antioxidants prolong shelf life and storage of gum base, finished gum ortheir respective components including fats and flavor oils. Antioxidantssuitable for use in gum base include butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulantssuch as Vitamin C, propyl gallate, other synthetic and natural types ormixtures thereof.

A chewing gum may include other conventional components such assweeteners, including bulk sweeteners, sugar sweeteners,sugar-substitute sweeteners, artificial sweeteners, high-intensitysweeteners, or a combination thereof. Bulk sweeteners may constitutefrom about 5 to about 95% by weight of the chewing gum, more typicallyabout 20 to about 80% by weight, about 30 to 70%, or about 30 to 60% byweight of the gum.

Useful sugar sweeteners are saccharide-containing components commonlyknown in the chewing gum art including, but not limited to, sucrose,dextrose, maltose, dextrins, trehalose, D-tagatose, dried invert sugar,fructose, levulose, galactose, corn syrup solids, and the like, alone orin combination.

Sorbitol can be used as a non-sugar sweetener. Other useful non-sugarsweeteners include, but are not limited to, other sugar alcohols such asmannitol, xylitol, hydrogenated starch hydrolysates, maltitol, isomalt,erythritol, lactitol and the like, alone or in combination.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. Non-limiting examples of highintensity sweeteners include sucralose, aspartame, salts of acesulfame,alitame, saccharin and its salts, cyclamic acid and its salts,glycyrrhizin, dihydrochalcones, thaumatin, monellin, sterioside and thelike, alone or in combination. In order to provide longer lastingsweetness and flavor perception, it may be desirable to encapsulate orotherwise control the release of at least a portion of the artificialsweeteners. Techniques such as wet granulation, wax granulation, spraydrying, spray chilling, fluid bed coating, conservation, encapsulationin yeast cells and fiber extrusion may be used to achieve desiredrelease characteristics. Encapsulation of sweetening agents can also beprovided using another chewing gum component such as a resinouscompound.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. The active level of artificial sweetener may vary fromabout 0.001 to about 8% by weight, and often ranges from about 0.02 toabout 8% by weight. When carriers used for encapsulation are included,the usage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used ifdesired.

A chewing gum and/or gum base may include one or morefillers/texturizers, such as magnesium and calcium carbonate, sodiumsulfate, ground limestone, silicate compounds such as magnesium andaluminum silicate, kaolin and clay, aluminum oxide, silicium oxide,talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulosepolymers, such as wood, and combinations thereof.

A number of other well-known chewing gum components may be present,including but not limited to waxes, fats, softeners, fillers, flavors,anti-oxidants, emulsifiers, coloring agents, binding agents andacidulates. The chewing gum may be provided with an outer coating, suchas a hard coating, soft coating, edible film-coating, or any combinationthereof.

In some aspects, nicotine is compounded along with other components ofthe gum base such that nicotine is substantially uniformly contained inthe gum base. Nicotine or a nicotine complex may be provided on anadsorbent such as finely divided silicic acid, amorphous silica,magnesium silicate, calcium silicate, kaolin, clays, crystallinealuminosilicates, macaloid bentonite, activated carbon, alumina,hydroxylapatite, microcrystalline cellulose, or any combination thereof.Nicotine may be encapsulated to provide a desired controlled orsustained release thereof. An example of a chewing gum that provides forsustained release of nicotine is described in U.S. 2007/0014887, thedisclosure of which is hereby incorporated by reference. Alternatively,isomyosmine may be infused into an outer portion of a chewing gum thancontains nicotine.

A similar release profile may be achieved via an oral dosage form suchas a tablet, capsule, or the like. For example, a tablet may have a corelayer containing nicotine to provide a sustained release thereof, and anouter layer containing isomyosmine to provide an immediate releasethereof. Other combinations are possible. For example, one or both ofthe layers may contain both isomyosmine and nicotine so that therespective active component(s) is released in both an immediate- and asustained release manner.

In other aspects, volatile delivery vehicles may be used foradministering the active component(s) including isomyosmine, such as aninhaler or e-cigarette. In still other aspects, the active component(s)are administered transmucosally such as via a nasal spray, ortransdermally such as via a transdermal patch.

A therapeutically effective amount of a therapeutic compound disclosedherein generally is in the range of about 0.001 mg/kg/day to about 100mg/kg/day. In aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be, e.g., at least 0.001mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45mg/kg/day, or at least 50 mg/kg/day. In other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 0.001 mg/kg/day to about 10mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet otheraspects of this embodiment, an effective amount of a therapeuticcompound disclosed herein may be in the range of, e.g., about 0.01mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 5 mg/kg/day to about 10mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day toabout 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day toabout 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100mg/kg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa substance addiction may comprise a one-time administration of aneffective dose of a pharmaceutical composition disclosed herein.Alternatively, treatment may comprise multiple administrations of aneffective dose of a pharmaceutical composition carried out over a rangeof time periods, such as, e.g., once daily, twice daily, trice daily,once every few days, or once weekly. The timing of administration canvary from individual to individual, depending upon such factors as theseverity of an individual's symptoms. For example, an effective dose ofa pharmaceutical composition disclosed herein can be administered to anindividual once daily for an indefinite period of time, or until theindividual no longer requires therapy. A person of ordinary skill in theart will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of apharmaceutical composition disclosed herein that is administered can beadjusted accordingly.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

The following example illustrates but does not limit the scope of thedisclosure set forth above.

EXAMPLE 1

This example describes experiments for determining monoamine oxidase(MAO) inhibition for isomyosmine and other alkaloids. MAOs are enzymeslocated on the outer membrane of mitochondria and are involved in thecatabolism of monoamine neurotransmitters. There are twowell-characterized isoenzymes: MAO-A, which predominantly catabolizesserotonin and norepinephrine, and MAO-B, which preferentiallycatabolizes benzylamine and phenylethylamine. Dopamine and tyramine aremetabolized by both isoforms.

To detect the activity of MAO, a luminescent method (MAO-Glo Assay kit,from Promega, Cat # V1401) was used. In this method, a MAO substrate (aderivative of beetle luciferin provided in the kit) is mixed with thecompound to be tested (in this case, myosmine and control compounds).Then, the MAO enzymes (either A or B, purchased separately) are added tothe mixture and incubated with the reaction for 1 hour at roomtemperature. The MAO enzymes, if not inhibited by the test compound,will convert the substrate into methyl ester luciferin. Finally, aluciferin detection reagent (provided by the kit) is added (20 minutesat room temperature) to stop the MAO reaction and convert methyl esterluciferin into D-luciferin. D-luciferin reacts with luciferase toproduce a luminescent signal, which is directly proportional to theD-luciferin concentration and thus the MAO activity: the greater theamount of light produced the higher the activity of MAO. The luminescentsignal is measured and recorded using a luminometer.

The following materials were obtained from Toronto Research Chemicals,North York, ON: isomyosmine, catalog # 1821350; myosmine, catalog #M835000; anabasine, catalog # A637175; and nornicotine, catalog #N756995. Anatabine was obtained from Emerson Resources, Norristown, Pa.

As positive controls for the experiment, clorgyline (awell-characterized potent inhibitor of MAO-A) and deprenyl (awell-characterized potent inhibitor of MAO-B) were used.

Results for MAO-A Activity

When the pure alkaloids isomyosmine, myosmine, anatabine, anabasine, andnornicotine were compared, isomyosmine was the most potent of the fivein inhibiting the enzymatic activity of MAO-A (FIG. 1). The way to readthis line graph is the following: a 100% activity means that the testcompound has no effect on the enzyme; a 0% activity means that the testcompound completely kills the enzyme. The more the curve is shifted tothe left, the greater the inhibition the test compound exerts on theenzyme. As can be seen in FIG. 1, the curve for isomyosmine is moreshifted to the left among the five alkaloids tested. A 2 mMconcentration (2,000 micromolar) gives an inhibition of about 50%. Thecurve for clorgyline, the positive control for the experiment, isgreatly shifted leftward.

Results for MAO-B Activity

Similar results were obtained when testing the five pure alkaloidsisomyosmine, myosmine, anatabine, anabasine, and nornicotine for theinhibition of MAO-B. Isomyosmine was the most potent among the fivealkaloids tested at inhibiting the activity of MAO-B, followed bymyosmine (FIG. 2).

EXAMPLE 2

This example shows that isomyosmine is effective to increase oxygensaturation (%) levels. As shown in FIG. 3, oxygen saturation (%) wasfound to dramatically increase in fourteen individuals when measured onehour after oral administration of isomyosmine at a dose of 100-300 mgdepending on body weight. Increasing oxygen saturation levels isbelieved to make isomyosmine particularly effective for treatingsubstance addictions, including tobacco/nicotine addictions, as well asaddictions to heroin, cocaine, opioids, methadone, d-methamphetamine,barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.For example, substances such as cocaine are known to cause blood vesselsto constrict, resulting in increased heartrate and blood pressure andincreased stress on the heart's ability to circulate blood and oxygenthrough the body. Increasing oxygen saturation levels may, among otherthings, counteract these types of effects associated with substanceabuse by increasing blood oxygen levels, aiding in the treatment of theunderlying addiction.

While the invention has been described with respect to specificexamples, those skilled in the art will appreciate that there arenumerous variations and permutations of the above described systems andtechniques that fall within the spirit and scope of the invention as setforth in the appended claims.

What is claimed is:
 1. A method of treating an addiction to opioidscomprising administering to an individual in need thereof apharmaceutical composition comprising a therapeutically effective amountof isomyosmine or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable vehicle therefor.
 2. The method of claim 1,wherein the pharmaceutical composition is administered via a capsule,tablet, or lozenge.
 3. The method of claim 1, wherein the pharmaceuticalcomposition contains isomyosmine or a pharmaceutically acceptable saltthereof in an amount from about 5 mg to about 1,500 mg.
 4. The method ofclaim 1, wherein the pharmaceutical composition contains isomyosmine ora pharmaceutically acceptable salt thereof in an amount from about 10 mgto about 1,200 mg.
 5. The method of claim 1, wherein the pharmaceuticalcomposition contains isomyosmine or a pharmaceutically acceptable saltthereof in an amount from about 50 mg to about 1,000 mg.
 6. The methodof claim 1, wherein the pharmaceutical composition contains isomyosmineor a pharmaceutically acceptable salt thereof in an amount from about100 mg to about 850 mg.
 7. The method of claim 1, wherein thepharmaceutical composition further comprises a second therapeutic agent.8. The method of claim 5, wherein the second therapeutic agent comprisesan anti-inflammatory compound.
 9. The method of claim 5, wherein thepharmaceutical composition contains the second therapeutic agent in anamount from about 5 mg to about 1,500 mg.
 10. The method of claim 1,wherein the pharmaceutical composition contains the second therapeuticagent in an amount from about 10 mg to about 1,200 mg.